In the energy-based fragmentation approach to computing the interaction energy between two molecules many interaction energies between small fragment molecules are required. Tens of thousands of these interactions are required if one of the molecules is as large as an enzyme. In this work we report the fragmentation of an entire enzyme and substrate and show that the majority of the small fragment molecule interactions can be accurately evaluated without the need to compute the ab initio interaction energy. This approach saves enormous amounts of cpu time and allows even more rapid evaluation of the total fragmentation interaction energy. (C) 2007 Elsevier B.V. All rights reserved.